The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

Dai, Shaodong; Crawford, Frances; Marrack, Philippa; Kappler, John W.

doi:10.1073/pnas.0805810105

Cited by 28 publications

(31 citation statements)

References 36 publications

(36 reference statements)

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“…This finding indicates that there are no major limitations in the length of peptides that can be incorporated into DR52b molecules and implies that the use of molecularly defined DR52b tetramers incorporating long peptides from defined protein regions, possibly preselected on the basis of the presence of binding motifs or through functional binding assays, may be an efficient strategy, allowing the rapid identification of immunodominant DR52b epitopes from a large number of antigens. These findings are also compatible with the fact that, in contrast to the strict length requirement of class I-bound peptides (8-10 mers) that need to perfectly fit a groove that is closed at both ends, often by adopting a kinked conformation, the class II binding groove, open at both ends, can easily accommodate long peptides (15-25 mers) that bind in an extended form (29,30).…”

Section: Discussionsupporting

confidence: 63%

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Ayyoub

Dojcinovic

Pignon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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MHC-peptide tetramers have become essential tools for T-cell analysis, but few MHC class II tetramers incorporating peptides from human tumor and self-antigens have been developed. Among limiting factors are the high polymorphism of class II molecules and the low binding capacity of the peptides. Here, we report the generation of molecularly defined tetramers using His-tagged peptides and isolation of folded MHC/peptide monomers by affinity purification. Using this strategy we generated tetramers of DR52b (DRB3*0202), an allele expressed by approximately half of Caucasians, incorporating an epitope from the tumor antigen NY-ESO-1. Molecularly defined tetramers avidly and stably bound to specific CD4 + T cells with negligible background on nonspecific cells. Using molecularly defined DR52b/ NY-ESO-1 tetramers, we could demonstrate that in DR52b + cancer patients immunized with a recombinant NY-ESO-1 vaccine, vaccineinduced tetramer-positive cells represent ex vivo in average 1:5,000 circulating CD4 + T cells, include central and transitional memory polyfunctional populations, and do not include CD4 + CD25 + CD127 − regulatory T cells. This approach may significantly accelerate the development of reliable MHC class II tetramers to monitor immune responses to tumor and self-antigens.S oluble MHC-peptide tetramers, allowing the direct visualization, characterization, and isolation of antigen-specific T cells, have become essential tools for T-cell analysis. MHC class I tetramers incorporating short CTL peptide epitopes, originally developed by Altman and Davis (1) have been generated for a large number of murine and human alleles, incorporating a variety of peptides of microbial, tumor, and self-antigen origin (2). The development of MHC class II tetramers, however, and particularly of those incorporating peptides from tumor and self-antigens, has been far less successful (3-5). One limiting factor is the high polymorphism of the human MHC class II molecules, especially those encoded by the DRB1 locus, the most frequently studied. Another limiting factor is the binding affinity of antigenic peptides derived from tumor and self-antigens, which is generally lower than that of peptides from pathogens.NY-ESO-1 (ESO), a tumor-specific antigen of the cancer/testis group frequently expressed in tumors of different histological types (6), is an important candidate for the development of generic cancer vaccines (7). In a recent vaccination trial using a recombinant ESO protein (rESO) administered with Montanide ISA 51 and CpG ODN 7909, we have observed induction of CD4 + T cell responses in all vaccinated patients (8). By assessing vaccineinduced CD4 + T cells, we have identified an immunodominant epitope , core region ESO 123-137 ) restricted by HLADR52b (DRB3*0202), an allele expressed by half of Caucasians (9). DRB3-, DRB4-, and DRB5-encoded molecules are less polymorphic than those encoded by DRB1, and are therefore attractive candidates for the development of generic MHC class II tetramers.Our initial attempts to const...

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Section: Discussionsupporting

confidence: 63%

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Ayyoub

Dojcinovic

Pignon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Within this sequence, a screening of the entire ESO sequence, using the MHC class II peptide-binding prediction algorithm RankPep (http://imed.med.ucm.es/Tools/rankpep.html), identified a sequence with high predicted binding capacity to DR52b, corresponding to peptide 127-135 (TVSGNILTI). Although the crystal structure of DR52b has not been yet resolved, some structural consideration on the potential contribution of single amino acids in the identified peptide to binding can be drawn based on previous analyses of natural peptides isolated from DR52 molecules and on the recently reported structure of the highly homologous DR52c molecule bound to a self-peptide derived from the Tu elongation factor (24,25). The most salient feature of the identified peptide is the amino acid N located in the central part of the sequence.…”

Section: Resultsmentioning

confidence: 99%

Vaccination with Recombinant NY-ESO-1 Protein Elicits Immunodominant HLA-DR52b-restricted CD4+ T Cell Responses with a Conserved T Cell Receptor Repertoire

Bioley

Dousset

Yeh

et al. 2009

Clinical Cancer Research

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Purpose: ESO is a tumor-specific antigen with wide expression in human tumors of different histologic types and remarkable spontaneous immunogenicity. We have previously shown that specific T H 1 and antibody responses can be elicited in patients with no detectable preexisting immune responses by vaccination with rESO administered with Montanide ISA-51 and CpG ODN 7909. The purpose of the present study was to characterize vaccine-induced ESO-specific CD4 + Tcell responses. Experimental Design: We generated CD4 + T cell clones from patient C2, who had the highest CD4 + Tcell response to the vaccine, and analyzed their fine specificity and HLA class II restriction to determine the recognized epitope.We then assessed the response to the identified epitope in all vaccinated patients expressing the corresponding HLA class II allele. Results: We found that ESO-specific CD4 + T cell clones from patient C2 recognize peptide ESO 119-143 (core region 123-137) presented by HLA-DR52b (HLA-DRB3*0202), a MHC class II allele expressed by about half of Caucasians. Importantly, following vaccination, all patients expressing DR52b developed significant responses to the identified epitope, accounting for, on average, half of the total CD4 + T cell responses to the 119-143 immunodominant region. In addition, analysis of ESO-specific DR52b-restricted CD4 + T cells at the clonal level revealed significant conservation of T cell receptor usage among different individuals. Conclusions: The identification of a DR52b-restricted epitope from ESO that is immunodominant in the context of vaccine-elicited immune responses is instrumental for the immunologic monitoring of vaccination trials targeting this important tumor antigen.

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“…DR52c (extracellular domains) with pHIR or pWIR covalently attached were cloned into a single baculovirus as previously described (21). V regions of the ANi2.3 TCR were fused to mouse C regions and expressed in baculoviruses as previously described (15,32,33).…”

Section: Methodsmentioning

confidence: 99%

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Yin

Crawford

Marrack

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T cell-mediated allergy to Ni++ is one of the most common forms of allergic contact dermatitis, but how the T-cell receptor (TCR) recognizes Ni ++ is unknown. We studied a TCR from an allergic patient that recognizes Ni ++ bound to the MHCII molecule DR52c containing an unknown self-peptide. We identified mimotope peptides that can replace both the self-peptide and Ni ++ in this ligand. They share a p7 lysine whose εNH 2 group is surface-exposed when bound to DR52c. Whereas the TCR uses germ-line complementary-determining region (CDR)1/2 amino acids to dock in the conventional diagonal mode on the mimotope-DR52c complex, the interface is dominated by the TCR Vβ CDR3 interaction with the p7 lysine. Mutations in the TCR CDR loops have similar effects on the T-cell response to either the mimotope or Ni ++ ligand. We suggest that the mimotope p7 lysine mimics Ni ++ in the natural TCR ligand and that MHCII β-chain flexibility in the area around the peptide p7 position forms a common site for cation binding in metal allergies.antigen presentation | hypersensitivity | peptide display library | crystal structure | metal recognition T -cell receptors (TCRs) made up of α-and β-chains have a very large number of ligands, including self-and foreign peptides, superantigens, lipids, small organic haptens, and metal ions. These ligands usually react with TCRs when they are bound to major histocompatibility complex (MHC) proteins. TCRs usually bind MHC/peptide combinations in similar orientations such that the TCR is aligned diagonally across the MHC/peptide, with the Vβ region of the TCR placed over the α1 α-helix of the MHCI heavy chain or of the MHCII α-chain and the Vα region placed over the α2 α-helix of the MHCI heavy chain or the β1 α-helix of the MHCII β-chain (1, 2). We (1, 3-5) and others (6-8) have suggested that germ line-encoded residues in the complementary-determining region (CDR)1 and CDR2 loops of the TCR variable regions are evolutionarily conserved for interaction with the MHC. These residues are also involved when natural killer T (NKT) cells recognize glycolipids bound to the nonclassical MHCI protein CD1d, and even when T cells recognize the non-MHC protein CD155 (9).It is noteworthy, however, that the presence of these evolutionarily conserved amino acids does not assure the conventional diagonal docking mode for TCRs on MHC molecules. For example, the NKT TCRs have a unique docking mode on CD1d (10, 11): Protein superantigens bridge TCRs to MHCII in a manner that prevents conventional TCR-MHCII interaction (12), and TCRs often dock to autoantigen peptides bound to MHCII in unusual orientations (13,14). Thus, in cases in which the structural details of the interaction between the TCR and its target are not known, we cannot be certain that the interaction will occur with the TCR in its usual orientation on MHC or not. Such is the case for the recognition of metal ions by TCRs (15 ++ when a particular unknown peptide(s) is bound to DR52c (18). Here, using a display library method we have previously describe...

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The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

Cited by 28 publications

References 36 publications

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Vaccination with Recombinant NY-ESO-1 Protein Elicits Immunodominant HLA-DR52b-restricted CD4+ T Cell Responses with a Conserved T Cell Receptor Repertoire

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

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The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

Cited by 28 publications

References 36 publications

Monitoring of NY-ESO-1 specific CD4 + T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Monitoring of NY-ESO-1 specific CD4 + T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Vaccination with Recombinant NY-ESO-1 Protein Elicits Immunodominant HLA-DR52b-restricted CD4+ T Cell Responses with a Conserved T Cell Receptor Repertoire

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

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Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers